Letrozole (20 μg/day, p.o.) exerts sex-specific reduction in thermoregulation during thermal challenge. (A) Facial temperature was measured via thermal camera during a 20-min thermal challenge. Representative images obtained 5 min and 20 min into the challenge are shown, along with the temperature reading. Percent change in temperature (°F) from the first min of the thermal challenge was plotted over time for females (B; Vehicle: n = 2; Letrozole: n = 4) and males (C; Vehicle: n = 5, Letrozole: n = 4). Letrozole treatment resulted in greater elevation in temperature across time for females only (p < .001). Error bars = SEM. [Gervais et al., JNeurosci (2018)]

A study in nonhuman primates by researchers at the University of Massachusetts and the University of Maryland School of Medicine has shown that the breast cancer drug letrozole has adverse effects on the brain. Letrozole is an aromatase inhibitor (AI) that is often given as adjuvant therapy to women with estrogen receptor-dependent breast cancer, but the treatment is linked with side effects including hot flashes and mood changes. The new studies, carried out in both male and female marmosets, showed that letrozole therapy caused behavior changes consistent with central nervous system (CNS) symptoms, and negatively impacted on the physiology of neurons in the brain’s hippocampus region.

Reporting their studies in the Journal of Neuroscience, Nicole Gervais, Ph.D., and colleagues say their findings highlight the need both for greater understanding of the mechanisms that underlie how AIs impact on brain function, and also “the development of new treatment approaches for breast cancer patients that minimize adverse effects on the brain.” Their paper is titled, “Adverse effects of aromatase inhibition on the brain and behavior in a non-human primate.”

Estrogens are produced through the conversion of testosterone by the enzyme aromatase, and patients with estrogen receptor-dependent breast cancer are commonly treated using adjuvant aromatase inhibitors, such as letrozole, to prevent this conversion. AI therapy is also used for men with prostate or breast cancers. Unfortunately, AI drugs can cause side effects including insomnia, depression, hot flashes, and memory problems that may be severe enough for patients to discontinue treatment, the authors wrote. “However, the mechanisms by which AIs give rise to these CNS symptoms remain unclear,” they pointed out, as studies in humans often lack proper controls and are hampered by confounding factors such as concurrent chemotherapy/radiotherapy treatment, stress, and disease stage. There have also not been any systematic analyses of sex-related differences in side effects.

The researchers’ reported study was designed to investigate whether continuous letrozole therapy in the marmoset as a nonhuman primate model would cause similar side effects to those observed in humans, but without the muddying effects of confounding factors. Marmosets and humans have similar brain structural and functional organization, the researchers pointed out, and prior studies indicated that the two species also share similarities in sleep and thermoregulation patterns, cognitive ability, and anxiety profiles.

Nine male and seven female marmosets were given letrozole in their puddings for four weeks, and the effects of treatment on cognition, anxiety, thermoregulation, brain estrogen content, and hippocampal pyramidal cell32 physiology were assessed. “This was the first study using a nonhuman primate to examine the effects of letrozole on brain and behavior,” the researchers wrote.

A wide range of tests showed that the treated animals did exhibit many of the same behavioral changes, including hot flashes and increased anxiety, that are experienced by women on AI therapy. The drug also affected spatial working memory and the functioning of neurons in the hippocampus.

Interestingly, assays showed that while letrozole therapy reduced peripheral levels of estradiol (E2), it unexpectedly increased estradiol levels in the hippocampus. Thermal challenge tests showed that letrozole therapy increased facial hot flashes, although only in females, “indicating some impact on hypothalamic activity, even though there were no changes to hypothalamic E2 levels.”

Electrophysiological recordings indicated that letrozole also adversely disrupted the intrinsic excitability of hippocampal neurons in both male and female animals. “Relative to controls, neurons from the letrozole-treated animals demonstrated reduced responsiveness to injected current, and lower spontaneous activity,” the researchers noted. “Taken together, these results suggest that 4 weeks of letrozole treatment mimics the detrimental effects of long-term ovarian hormone deprivation on IE and spontaneous activity.”

The results in a nonhuman primate corroborate many of the symptoms reported by women taking AIs and reveal detrimental effects of these treatments on the brain, in part through elevated hippocampal E2 levels,” the researchers concluded. “Future studies are needed to elucidate the precise mechanisms by which AIs compromise the CNS.”

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